The overarching goal of this study is to recruit transgender youth (TGY; youth who feel that their true gender is different than their biological sex at birth) into a longitudinal study and examine substance use and associated mental health disparities. This is a very nascent field. To date there are only a handful of within- group descriptive studies reporting high rates of substance use and mental health problems among TGY (Garofalo et al., 2006; Grossman & D'Augelli, 2006), and these studies are largely focused on older teenagers and young adults and male-to-female TGY. In addition, there are only two peer-reviewed disparities studies in the literature (comparing TGY to non-TGY) and both were published within the past year (Reisner et al., 2014, Fergusson et al., 2014). Results from these studies showed that compared with non-TGY, TGY are at increased risk for substance use, depression, anxiety, and suicidality. Yet these seminal studies are limited by their cross-sectional design, absence of measures that can describe and understand transgender-related identity and developmental processes, and other important assessment tools such as face-to-face psychiatric diagnostic interviews and information regarding transgender healthcare access. Thus the primary and overarching goal of this study is to begin to explore and fill these gaps in the adolescent literature. Our specific aims are: (1) to identify and describe substance use and associated mental and behavioral health problems (e.g., depression, suicidality, HIV risk behavior) over time among TGY; and (2) to identify and examine explanatory mechanisms (risk and protective factors) of substance use disparities among TGY (e.g., victimization, social isolation, depression, family and friend support). Currently, there are no evidence-based interventions to guide TGY and families through gender transition care. Findings from this study will provide important preliminary data to inform clinicians working with TGY and will guide the development of an intervention for TGY to promote positive outcomes during the process of transitioning.